A fibrin sealant, which is called a fibrin glue or a fibrin tissue adhesive, uses a human body blood clotting mechanism. More specifically, blood clotting is made through chain reactions of blood clotting factors, and fibrinogen, Factor XIII, and thrombin, or the like, are involved in a final step of the clotting pathway. Here, the fibrin sealant use the principle that Factor XIII, fibrinogen, calcium chloride, and thrombin are mixed to form a fibrin polymer, and at this time, Factor XIII serves to crosslink the fibrin polymers, such that the fibrin polymer is converted into insoluble fibrin polymer.
The fibrin sealant applies the blood clotting mechanism described above to an adhesive. That is, the fibrin sealant is based on the principle that when a wound, or the like, occurs in tissue, fibrinogen is released together with blood components from capillary blood vessels around the wounded tissue to form fibrin, thereby adhering to the surroundings of the wound. Applications of the fibrin sealant for treatment purpose such as adhesion to tissue and hemostasis, playing a supportive role for healing a wound, or the like, have been continuously widened. The fibrin sealant has biological advantages such as not having coagulation disorder with platelets, excellent histocompatibility, and appropriate absorption, or the like, in addition to physical advantages such as rapid adhesion, not being affected by moisture of an adhering portion, or the like, such that the fibrin sealant has been significantly spotlighted as the next-generation medical adhesive.
Clinical studies of the fibrin sealant on a suture of a peripheral nerve, a suture of micro-vessel using tissue adhesion action of the fibrin sealant based on the advantages of the fibrin sealant as described above has been conducted in Europe, and the fibrin sealant has been used in vascular surgery, surgery, neurosurgical operation, adhesion of bone, or the like, as an adhesive for surgery in Japan.
In order to prepare this fibrin sealant, initially, thrombin, which is one of the fibrin components, was separated from bovine blood plasma to be used (Patent Document 1, U.S. Registration Pat. No. 4,627,879) in Europe, but was not sold due to a safety problem, or the like, outside of Europe. In addition, although fibrin sealant formulations using autologous blood (See U.S. Pat. Nos. 4,714,457, 5,030,215, or the like) has been developed, since a blood sampling process and additional manufacturing processes were required, it was significantly inconvenient to be clinically used.
Therefore, in the fibrin sealant prepared from human blood plasma to be commercially sold, safety against a virus should be secured and the clinical use should be convenient.
Recently, as the fibrin sealant, a freeze-dried type fibrin sealant and a frozen-liquid type fibrin sealant have been marketed. In the freeze-dried type fibrin sealant, since a dissolution time of fibrinogen was long and it took a relatively long time to be reconstituted, it was inconvenient in that the freeze-dried fibrin sealant should be rapidly used. On the other hand, the frozen-liquid product has an advantage in that it takes a relatively short time to be actually used as compared to the freeze-dried type product. A representative product is Tisseel (Baxter Healthcare Corp.). Tisseel is being sold as a pre-filled type product that may be frozen in a liquid state, that is, a ready-to-injection form product that may be immediately injected, and estimated as a product significantly reducing a preparation time for use.
However, in the case of the frozen-liquid product, there are disadvantages that solvent/detergent (S/D) treatment and heat treatment using steam should be performed in order to remove any virus derived from the blood (See U.S. Pat. No. 5,962,405 and Tisseel data (www.baxter.com)).
Particularly, there was inconvenience in that freeze-drying should be performed in the middle of the process in order to perform the thermal-treatment using steam (See European Patent Publication No. 345246 and European Patent Publication No. 159311). In addition, since a method of freeze-drying fibrinogen to dissolve fibrinogen is used in order to obtain highly concentrated fibrinogen, there is inconvenience in that the freeze-drying process should be performed in order to obtain fibrinogen solution having a high concentration, particularly, a concentration of 70 mg/mL or more that is required to prepare the fibrin sealant.
A technology capable of solving the problem in the process of preparing the fibrin sealant currently used as described above and more economically and easily preparing the fibrin sealant, particularly, a technology capable of more economically, easily, and highly concentrating fibrinogen to prepare the fibrin sealant has been urgently required.